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AN EVIDENCE-BASED APPROACH TO TREATING OTITIS MEDIA
Pediatric Clinics of North America - Volume 43, Issue 6 (December 1996) - Copyright © 1996 W. B. Saunders Company
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PEDIATRIC OTOLARYNGOLOGY
AN EVIDENCE-BASED APPROACH TO TREATING OTITIS MEDIA
Richard M. Rosenfeld MD, MPH
From the Department of Otolaryngology, State University of New York Health Science Center at Brooklyn; and the Division of Pediatric
Otolaryngology, Department of Otolaryngology, University Hospital of Brooklyn and The Long Island College Hospital, Brooklyn, New York
Patient care is ideally based on evidence derived from the best available studies. The practitioner who treats children with otitis media is
fortunate in this regard, because a wealth of high quality clinical trials and epidemiologic studies have been published. Further, much of
this evidence has been synthesized into bottom-line efficacy estimates and treatment guidelines that deal specifically with the medical
management of otitis media. [70] [71] [72] [79] [84]
Otitis media implies the presence of a middle ear effusion (MEE), or fluid in the middle ear space (Table 1) . MEE accompanied by acute
symptoms is called acute otitis media (AOM). AOM is caused by ascent of viral or bacterial pathogens from the nasopharynx into the
middle ear during an upper respiratory infection. MEE without associated symptoms is called otitis media with effusion (OME). OME
may arise as a sequelae to AOM or spontaneously; the latter is also called silent otitis media when it occurs as an incidental finding during
physical examination or screening tests. The nonspecific term ear infection applies to AOM and OME, because pathogenic bacteria
generally are present in the middle ear with both conditions. [63]
This article presents an evidence-based approach to managing otitis media. Rational management begins by understanding the natural
history of untreated otitis media and knowing what to expect from medical therapy. [74] Next, a stepwise treatment plan is presented,
based on epidemiologic studies, systematic reviews of clinical trials, and personal experience as a pediatric otolaryngologist who has
successfully treated thousands of children with otitis media.
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TABLE 1 -- OTITIS MEDIA DEFINITIONS AND EPIDEMIOLOGY
Otitis Type
Definition
Comment
MEE
Fluid in the middle ear space,
regardless of cause; hearing loss
may be present depending on the
volume of fluid
Diagnosis requires assessment
of middle ear function by
pneumatic otoscopy or
tympanometry
Myringitis
Erythema of the tympanic membrane,
without MEE; similar appearance
occurs from dilation of tympanic
membrane vessels when crying
during otoscopy
Most often viral but may be
seen in early stages of AOM
or during resolution; does
not require antibiotic
treatment
AOM
MEE with rapid onset of one or more
of the following: otalgia, ear pulling,
otorrhea, fever, irritability, anorexia,
vomiting, or diarrhea
Most frequent diagnosis made
by pediatricians; affects
about 50% of children by
age 1 year, 65% by age 2
years, and 70% by age 3
years
OME
MEE without signs or symptoms of
acute infection; chronic OME
implies duration longer than 2 to 3
months
Occurs in both healthy children
and following an episode of
AOM; 15% prevalence with
seasonal variations
Recurrent AOM
At least three episodes of AOM in the
past 6 months, or four episodes in
12 months; also called the otitis-prone condition
Affects about 15-30% of
children; MEE may persist to
varying degrees between
episodes
AOM = acute otitis media, OME = otitis media with effusion.
Address reprint requests to
Richard M. Rosenfeld, MD, MPH
Department of Otolaryngology
Long Island College Hospital
340 Henry Street
Brooklyn, NY 11201
WHAT TO EXPECT FROM NATURAL HISTORY
Otitis media has a favorable natural history. Data from observational studies [80] [86] and from control groups in randomized control trials [71] [72]
[79] [84] show that most cases of AOM and OME resolve without treatment (Table 2) . For example, in two recent well-designed clinical trials,
86% and 92% of placebo-treated children with AOM were clinical cures. [15] [38] To appreciate the impact of natural history on perceptions of
treatment efficacy, consider the following:
If 100 children with AOM caused by amoxicillin-resistant bacteria are nonetheless treated with amoxicillin, how many will have
complete clinical resolution in 7 to 14 days? About 70% to 90% will be "cured" as shown in Table 2 . The child's immune system cares
little if the bacteria are resistant to the drug; it mounts an effective inflammatory response regardless.
If 100 children with persistent OME after AOM have chiropractic manipulation for 1 month, how many will resolve? About 60%,
assuming that chiropractic is no better than placebo. If "treatment" is continued for an additional 2 months, the "cure" rate will rise to 90%.
If 100 children with silent OME detected in a school screening program receive homeopathic treatment for 3 months, how many will
resolve? About 65%, assuming that homeopathy is no better than placebo. If "treatment" is continued for an additional 3 months, 85% will
be "cured" of effusion.
If 100 children with recurrent AOM take garlic concentrate for 12 months,
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how much will the frequency of AOM diminish? About 1.5 to 3.0 annual episodes will be "prevented," assuming that garlic is no better
than placebo.
TABLE 2 -- NATURAL HISTORY OF UNTREATED OTITIS MEDIA
Otitis Type
Population Studied
Approximate Rate
of Spontaneous
Resolution
AOM
[72]
Children receiving placebo or no drug in
antibiotic trials of initial empiric
therapy
70-90% at 7-14 days
OME
[80]
Children with residual middle ear
effusion following an episode of AOM
60% at 1 month
80% at 2 months
90% at 3 months
*
OME
[86]
Children with OME of unspecified
duration detected by tympanometric
screening
65% at 3 months
85% at 6 months
OME
[71] [79] [84]
Children receiving placebo or no drug in
antibiotic trials, most with OME
duration 4-8 weeks
15-30% at 2-8 weeks
Children receiving placebo for
prophylaxis of recurrent AOM
1.5-3.0 episodes per
year, decrease in
AOM
Recurrent AOM
[84]
* Resolution of asymptomatic middle ear effusion not required for cure.
The examples above are provided to illustrate the favorable natural history of otitis media, not to demean alternative medicine. Alternative
medicine, however, is used by 11% of children, [76] most often for chronic disease (e.g., otitis media) and without the knowledge of the child's
physician. [23] Because most cases of otitis media are self-limited, the efficacy of alternative medicine--or any intervention--can be judged only by
prospective clinical trials with a parallel control group. Without a thorough appreciation of the spontaneous course of untreated otitis media,
practitioners and caregivers can easily mistake natural history for treatment effects.
Short-term spontaneous resolution of AOM most likely reflects the host immune response and local inflammatory reaction. This phenomenon is
appreciated in Denmark, Norway, Sweden, and the Netherlands, where most children 2 years of age and older with nonsevere AOM are not
treated initially with antibiotics. [28] [36] Unfortunately, the middle ear inflammation that accompanies AOM can result in lingering OME after
symptom relief. Spontaneous clearance of residual OME, however, occurs in 90% of children within 3 months (Table 2) as inflammation subsides
and the eustachian tube reopens. Because OME is so common following antibiotic treatment for AOM, clearance of the fluid is unnecessary for a
successful outcome in efficacy trials. [72]
Long-term spontaneous resolution of recurrent AOM and chronic OME most likely reflects a gradual maturation in the child's immune system and
eustachian tube function. Further, because most patients seek medical care when at their worst, the next event is often a change for the better,
irrespective of treatment given (regression to the mean). [21] Children enter clinical trials for recurrent AOM with three to five annual episodes but
average only one to two episodes during the next 12 months when treated with placebo. [84] A similar
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pattern has been reported for children with recurrent sore throat after entering a tonsillectomy trial.
[59]
WHAT TO EXPECT FROM MEDICAL TREATMENT
More than 250 clinical trials have sought to define the impact of medical treatment on otitis media. Systematic literature reviews (meta-analysis)
of published randomized control trials yield the mean estimates of treatment efficacy listed in Table 3 . These data have been summarized as
follows [74] :
Antibiotics have a modest but statistically significant impact on the treatment of otitis media. About seven children with AOM or OME
must be treated to improve a single child, beyond what would occur from natural history alone. Despite this modest effect, some studies
show faster symptom relief with antibiotics than with placebo. [15] [38] [51]
Antibiotics have a modest but statistically significant impact on the prevention of otitis media. Preventing a single episode of AOM
requires that prophylaxis be given to one child for 9 months, or to nine children for 1 month.
Subgroup analyses have not demonstrated a significant increase in clinical efficacy for newer, more expensive drugs over established
standards, such as amoxicillin, when treating AOM or OME.
Combining an antibiotic with an oral steroid seems promising, but the evidence is sparse, inconsistent, and just misses statistical
significance.
Antihistamine and decongestant preparations, alone or in combination, have comparable efficacy to placebo. Consequently, there is no
justification for their use when treating OME, unless they are consciously administered to achieve a placebo effect.
TABLE 3 -- WHAT TO EXPECT FROM MEDICAL TREATMENT FOR OTITIS MEDIA
Otitis Type
Treatment Group
Versus
Control Group
Impact of Therapy
Outcome
Time
Statistically
Significant?
Yes
No
No
No
AOM
[72]
Abx versus placebo or
no drug
Penicillin versus
amoxicillin
Cefaclor versus
amoxicillin
Cefixime versus
amoxicillin
14% increase in
symptom relief
Trend favoring amoxicillin
Equivalent outcomes
Trend favoring amoxicillin
7d-14d
7d-14d
7d-14d
7d-14d
OME
[1]
Abx versus placebo or
no drug
14% increase in shortterm cures
10d-2m
Yes
Steroid-abx versus
abx alone
Trend favoring steroidabx
7d-14d
No
Antihistamine/
decongestant
versus placebo
Equivalent outcomes
2w-12w
No
Abx prophylaxis
versus placebo
0.11 episode/month
decrease
10w-2y
Yes
Sulfisoxazole
prophylaxis versus
placebo
0.20 episode/month
decrease
10w-2y
Yes
Recurrent
AOM [84]
Abx = antibiotic.
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Qualification of these comments is required. First, the results apply only to clinical efficacy; the ability of antibiotics to destroy middle ear
pathogens-- bacterial efficacy--may exceed that suggested by clinical outcomes. [45] Second, bacterial resistance patterns are changing, with an
increasing prevalence of multidrug-resistant Streptococcus pneumoniae [49] and beta-lactamase-producing Haemophilus influenzae and Moraxella
catarrhalis. [11] Older studies may have included children with bacteriology different than those encountered today, but the high rate of
spontaneous otitis media resolution makes it unlikely that this would substantially alter results. Finally, because the results reflect mean treatment
effects, individual patients may vary in their response to antibiotics.
The modest impact of antibiotics on otitis media argues for judicious treatment, not therapeutic nihilism. Although natural history--not antibiotics- accounts for most clinical resolution of AOM, delayed suppurative complications (e.g., mastoiditis) are exceedingly rare compared with the
preantibiotic era. For OME the modest short-term benefit of antibiotics makes it unlikely that prolonged or repetitive therapy will offer any
advantage; therefore, treatment should be limited to one or two drugs spaced at least several weeks apart. For recurrent AOM, the modest benefits
of antibiotic prophylaxis probably are exceeded by the risk of accelerated bacterial resistance, particularly in group day care, where horizontal
transmission of resistant organisms is common. [13] Prophylaxis might be reserved for selected children not enrolled in day care, with frequent or
severe infections.
SELECTING AN ANTIBIOTIC FOR OTITIS MEDIA
Recommended drugs for managing otitis media are listed in Table 4 . The most important decision concerns which class of antibiotic to use-prophylactic, first-line, second-line, or third-line--not which agent to administer within a class. Prophylactic antibiotics are indicated only for
recurrent AOM as defined in Table 1 ; there is no benefit to long-term prophylaxis for OME. [66] [83] First-line antibiotics are used for initial
empiric therapy of uncomplicated AOM or OME. Second-line drugs are indicated for initial treatment failures, complicated infections, and
children with ipsilateral conjunctivitis suggesting H. influenzae infection. [12] Because no comparative differences in clinical outcomes have been
reported among second-line antibiotics, drug choice should be based on cost, convenience, and tolerance.
If the prevalence of beta-lactamase-producing pathogens is rising, [11] [25] how can amoxicillin still be the drug of choice for initial treatment of
otitis media? It is because of a favorable natural history, which occurs independently of bacterial resistance patterns. [64] AOM treatment failures
occur despite susceptible bacteria, and successes occur despite bacterial resistance. [61] [72] For example, if 20% of children with uncomplicated
AOM have beta-lactamase-producing bacteria, resistance will account for failure in only 4% of cases because spontaneous resolution is 80%. This
theory assumes that 35% of AOM is caused by S. pneumoniae, 30% by H. influenzae, and 10% by M. catarrhalis, of which approximately 0%,
35%, and 90% produce beta-lactamase. [10]
Penicillin-resistant S. pneumoniae are rising in prevalence, particularly among children in group day care.
antibiotic is
[81]
Recent use of a beta-lactam
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TABLE 4 -- RECOMMENDED DRUGS FOR MEDICAL MANAGEMENT OF OTITIS MEDIA
Category; Generic (Trade) Names
Frequency,
Duration
Pediatric Daily
Dosage
Comments
Prophylactic antibiotics
Amoxicillin (Amoxil)
QD, 1-6m
20 mg/kg/d
Must refrigerate; refill every 2 weeks
Sulfisoxazole (Gantrisin)
QD, 1-6m
50-75 mg/kg/d
No refrigeration necessary
Amoxicillin (Amoxil)
TID, 10d
40 mg/kg/d
Still the drug of choice for initial therapy
Trimethoprim-sulfamethoxazole,
(Bactrim; Septra)
BID, 10d
1 tsp each 10 lb body When child is penicillin-allergic
weight
Amoxicillin-clavulanate
(Augmentin)
TID, 10d
40 mg/kg/d on
amoxicillin
Broad spectrum, but 15-20%
gastrointestinal upset
Azithromycin (Zithromax)
QD, 5d
10 mg/kg day 1; 5
mg/kg
days 2-5
Suspension can be given without
regard for food; capsules cannot
Cefprozil (Cefzil)
BID, 10d
30 mg/kg/d
Not approved before 6 mo of age
Cefpodoxime (Vantin)
QD, 10d
10 mg/kg/d
Broad spectrum, convenient dosing
Ceftibuten (Cedax)
QD, 10d
9 mg/kg/d
Broad spectrum, convenient dosing
Cefuroxime (Ceftin)
BID, 10d
30 mg/kg/d
Broad spectrum, but bitter taste
Clarithromycin (Biaxin)
BID, 10d
15 mg/kg/d
Broad spectrum, well tolerated
Loracarbef (Lorabid)
BID, 10d
30 mg/kg/d
Must give 1 hour ac or 2 hours pc
Clindamycin (Cleocin)
TID, 10d
8-12 mg/kg/d
Superb for resistant pneumococcus
Ceftriaxone (Rocephin)
QD, 1-5d
50-75 mg/kg/d IM
Useful for refractory acute otitis media
1 mg/kg/d × 5 d; ½
mg/kg/d
×5d
Give together with an antibiotic
First-line antibiotic therapy
Second-line antibiotic therapy
Third-line antibiotic therapy
Oral steroids
Prednisolone (Pediapred,
Prelone)
QD, 10d
ac = before meals, pc = after meals.
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also a risk factor. Amoxicillin achieves MEE levels effective against 90% of pneumococci with intermediate penicillin resistance, contrasted with
the inadequate levels achieved by most second-line drugs. [39] [53] This helps explain reports of pneumococcal bacteremia and meningitis during
initial treatment of AOM with cefixime [57] and clarithromycin. [68] For highly penicillin-resistant pneumococci, the only orally administered
antibiotic with adequate MEE levels is clindamycin, [39] [53] hence its listing as a third-line agent in Table 4 . Note that Clostridium difficile colitis
can occur with any broad-spectrum antibiotic and is no more common with clindamycin than with amoxicillin or the cephalosporins. [26] A
pediatric suspension of clindamycin is available.
Single-dose intramuscular ceftriaxone is no "magic bullet" for AOM, and its impact on OME has not been studied. Recent trials show a mean 79%
clinical improvement with single-dose ceftriaxone versus 84% improvement with 10 days of amoxicillin, [33] cefaclor, [17] or trimethoprimsulfamethoxazole. [4] [58] Although the difference is not statistically significant, we cannot conclude with certainty that 79% resolution offers any
benefit beyond natural history. Further, liberal use of a potent, broad-spectrum antibiotic, such as ceftriaxone, may accelerate bacterial resistance.
[81] Consequently, the author suggests reserving ceftriaxone for third-line therapy (e.g., second-line treatment failures) and for AOM with
intracranial or intratemporal complications (e.g., meningitis).
The optimal duration and dosing of antibiotic therapy is uncertain. Amoxicillin-treated children with AOM had similar outcomes with 3-day
versus 7-day, [37] 3-day versus 10-day, [18] 5-day versus 10-day, [35] and 10-day versus 20-day regimens. [43] Furthermore, clinical resolution is
unaltered when amoxicillin is given once, twice, or thrice daily. [50] [65] These negative findings are not surprising given that the majority of AOM
clinical resolution occurs by natural history and that there is no worldwide consensus on whether antibiotics are necessary for most cases. Limited
data are available for OME, but the findings for AOM most likely apply. Because efficacy estimates (see Table 3) are derived mostly from clinical
trials using 10-day therapy and dosing schedules approved by the manufacturer, the author recommends that practitioners do the same.
Individualized variations in duration and dosing, however, are unlikely to significantly alter results.
STEPWISE APPROACH TO AOM
AOM remains the most common childhood disorder seen in physicians' offices and in hospital emergency departments. Annual visitation rates for
AOM have more than doubled from 1975 to 1990, with a corresponding rise in antibiotic drug prescription rates. Although amoxicillin is currently
prescribed twice as often as other drugs, a disturbing trend has occurred toward increased use of more expensive, broad-spectrum agents, such as
cephalosporins. This trend may contribute to rising health care costs and the emergence of antibiotic resistance. [48]
Aggressive treatment for AOM with expensive, broad-spectrum antibiotics reflects unrealistic expectations on the part of practitioners and
caregivers (Table 5) . [74] There is no benefit to initial empiric therapy with second-line drugs (see Table 4) over first-line agents, because 70% to
90% of AOM improves clinically without treatment. For the 90% to 95% of children who respond favorably to antibiotics, about 80% of cures are
from spontaneous resolution and only 10% to 15% from drug therapy. [72] The primary benefit of antibiotic treatment on AOM is most likely to
reduce the incidence of delayed suppurative complications,
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TABLE 5 -- STEPWISE APPROACH TO MANAGING ACUTE OTITIS MEDIA
Step
Comment
1. Select an antibiotic
Base decisions on cost, convenience, and tolerance,
not bacterial spectrum; use a second-line
antibiotic (see Table 4) if otitis-conjunctivitis
syndrome or early relapse of prior AOM
2. Define realistic expectations
About 90-95% symptom relief, excluding
asymptomatic MEE, within 10-14 days (80% from
spontaneous resolution, 10-15% from antibiotic);
main purpose of antibiotic is to reduce chance of
suppurative complications
3. Retreat clinical failures
Use a second-line antibiotic (see Table 4) if
symptoms persist; retreatment with first-line drugs
is less effective
4. Use tympanocentesis sparingly
Reserve for retreatment failures with severe
symptoms, or those refractory to third-line
antibiotics (see Table 4) ; no role for
tympanocentesis earlier in therapy
5. Monitor residual OME
Residual OME after AOM is the rule, not the
exception, and may last for several months;
consider reating with a second-line antibiotic (see
Table 4) after 6-8 weeks
similar to the impact of antibiotics on group A streptococcal pharyngitis. For example, acute mastoiditis complicated more than 20% of cases of
AOM in the preantibiotic era [75] but now has an incidence of less than 0.1%. [52]
Persistent AOM following treatment is most often secondary to middle ear inflammation after bacteria are killed, either by antibiotics or by the
host immune response. Other causes of persistent AOM include bacterial resistance to the initial antibiotic [61] and viral pathogens or copathogens
in the middle ear. [19] Because the cause of failure generally is not apparent, continued antibiotic therapy is indicated to cover any persistent
bacteria that may predispose the child to suppurative complications. Retreatment with a second-line antibiotic is more effective (60-90% clinical
resolution) than retreatment with amoxicillin or trimethoprim-sulfamethoxazole (25-40% clinical resolution). [62]
Penicillin-resistant S. pneumoniae may cause persistent AOM, particularly in otitis-prone children fewer than 2 years of age who attend group day
care. [8] [85] Clindamycin is the most effective orally administered antibiotic for resistant pneumococcus; about two thirds of highly resistant
strains also may be susceptible to intramuscular ceftriaxone (not single-dose therapy). [8] High-dose amoxicillin (60-80 mg/kg/d) also has been
proposed and may be appropriate first-line therapy for high-risk children in communities with endemic penicillin resistance. [14] Myringotomy
should be reserved for cases refractory to second-line and third-line antibiotics and for children with immune dysfunction or multiple drug
allergies. When used as initial therapy for severe AOM, however, myringotomy is no more effective than antibiotics alone. [38]
Residual OME after resolution of acute symptoms is a consequence--not a complication--of AOM. About 50% of children in clinical trials have an
asymptomatic effusion following treatment for AOM, unrelated to the duration or bacterial spectrum of the initial antibiotic. [43] [72] Fortunately,
about 90% of episodes resolve spontaneously within 3 months unless acute reinfection occurs (see Table 2) . Treatment of residual OME with
additional antibiotics has a modest impact
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on short-term cures (see Table 3) , but the impact on long-term cure is uncertain.
line antibiotic should be used for stubborn effusions following AOM.
[84]
Therefore, at most, one first-line antibiotic and one second-
STEPWISE APPROACH TO OME
The first step in managing OME is diagnosing its presence. Many children with OME have a normal-appearing tympanic membrane, making it
easy to miss an effusion unless middle ear function is assessed. Tympanometry is used most often in this regard, although pneumatic otoscopy has
comparable accuracy. [82] The positive predictive value for OME of a flat (type B) tympanogram (i.e., the likelihood that an effusion is present if
the tympanogram is abnormal) is between 49% and 99%. A false-positive tympanometry result can be caused by impacted cerumen, a foreign
body, tympanic membrane perforation, or improper placement of the instrument tip on the ear canal wall. Because of these limitations, pneumatic
otoscopy is recommended for primary diagnosis of OME with tympanometry as a confirmatory test. [79]
Detecting OME does not imply a need for active treatment (Table 6) . About 90% of effusions less than 2 to 3 months' duration resolve without
treatment within a few months (see Table 2) . OME of longer duration has cure rates of only 15% to 30% from watchful waiting (see Table 2) ,
even when observation is extended to 30 months. [41] Regardless of OME duration, the impact of antibiotic therapy is marginal (see Table 3) and
short-lived; antibiotic-treated and placebo-treated children have comparable outcomes several weeks after completing therapy. [44] Aggressive
antibiotic treatment of OME is therefore difficult to justify, especially because the incidence of delayed suppurative complications is near
TABLE 6 -- STEPWISE APPROACH TO MANAGING OTITIS MEDIA WITH EFFUSION
Step
Comment
1. Be patient
Most cases resolve without treatment (see Table 1) , particularly when
following a
recent episode of AOM
2. Use antibiotics sparingly
Antibiotics boost short-term resolution by
about 15% and therefore benefit only one
child of every seven treated; do not use
repetitive, prolonged, or prophylactic
antibiotics
3. Put the odds in your favor
Limit passive smoke exposure; treat sinusitis;
control food and inhalant allergies
4. Test hearing after 3 months
Any child can be tested, regardless of age;
tube insertion is recommended for bilateral
effusions lasting 4 months or longer with an
associated hearing loss
5. Consider steroid-antibiotic therapy
Most effective when hearing is normal and
child is not otitis-prone; observe varicella
precautions (see text)
6. Fit the punishment to the crime
Chronic effusions without hearing loss can be
managed expectantly; consider surgery if
accompanied by otalgia, recurrent AOM,
retraction pockets, speech problems, or
antibiotic intolerance
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zero. Autoinflation of the eustachian tube, by means of a plastic nasal cannula and attached balloon, is a harmless adjunct to watchful waiting that
may be tried in older children. [7] [77] Prophylactic antibiotics and antihistamine-decongestant preparations offer no benefits beyond placebo
therapy.
Clinicians can improve the odds of OME resolution by modifying risk factors and controlling concurrent illness. The risk of getting AOM or OME
is increased with passive smoke exposure, group day-care attendance, and bottle-feeding rather than breast-feeding infants. [79] The associations,
however, are modest (relative risk about 2.0), and many breast-fed children cared for at home by nonsmokers still obtain otitis media. Nonetheless,
efforts to limit smoke exposure seem prudent, particularly for children in group day care, in which 18% of cases of OME may be attributable to
parental smoking. [24] Because allergy to milk proteins may cause middle ear inflammation, [6] the author recommends a milk-free diet for several
weeks as a diagnostic trial in children fewer than 2 years of age. In older children with OME, concurrent illnesses, such as sinusitis and allergic
rhinitis, should be brought under optimal control.
A child with bilateral OME for 3 months or longer should undergo hearing evaluation. [79] No child is too young to test, including infants fewer
than 6 months of age. OME generally causes a mild conductive hearing loss (27 dB hearing level [HL]), but 20% of ears have a pure-tone average
of more than 35 dB HL. [27] Although the relationship between early OME and language development is controversial, the literature supports a
direct connection between hearing and language with middle ear effusion as an intermediate variable. [28]
Placement of tympanostomy tubes is recommended for children with 4 to 6 months of bilateral OME and hearing loss, defined as 20 dB HL or
higher for the better ear. [79] Hearing levels obtained in a soundproof booth, however, may underestimate the auditory impact of OME on children
in real-world listening environments. For example, the ability of children to recognize words presented at soft levels or with background noise
deteriorates when OME is present, even when hearing levels are normal. [69] Difficulties in word recognition may cause behavioral problems, poor
attention span, or poor school performance. Therefore, affected children with bilateral OME and normal hearing may still benefit from
tympanostomy tubes on a selective basis. Finally, hearing levels fluctuate relative to the volume of middle ear fluid and should be periodically
retested when deferring surgery because of normal hearing.
Steroid therapy is not recommended for children 3 years of age or younger with OME [79] but may be used selectively in older children as a lastresort medical alternative to surgery. [73] Oral prednisone or prednisilone (see Table 4) is given concurrently with a second-line antibiotic,
provided that there has been no varicella exposure for 3 weeks and there is no coexisting AOM or sinusitis. Children who get varicella while
taking steroids should discontinue the drug and be considered for oral acyclovir therapy to minimize the likelihood of severe disease. [1] Relapse
of OME occurs in 40% of initial responders following steroid-antibiotic therapy, yielding a 6-month cure rate of about 25%. Children without
hearing loss or recurrent AOM seem to have the most favorable outcomes. [73]
Decisions concerning the relative merits of ongoing medical therapy for OME versus surgical intervention (i.e., tympanostomy tubes) must be
individualized (Table 7) . Children with asymptomatic OME who also have normal hearing, speech, school performance, and tympanic membrane
appearance may be monitored with extended periods of watchful waiting. The key word in the preceding sentence is monitored; implicit in a waitand-see approach is interval otoscopy and audiometry every 3 to 4 months to detect changes in hearing status or the structural integrity of the
tympanic membrane. In contrast, a hearing-impaired
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TABLE 7 -- FACTORS INFLUENCING DECISIONS FOR OR AGAINST SURGERY FOR OME
Factor
Favors Alternatives to
Surgery
Favors Surgery
Epidemiology
Laterality of OME
Bilateral
Unilateral
Duration of OME
Less than 3 months
3 months or longer
AOM history
Recurrent AOM
Infrequent AOM
Daytime environment
Group day care
Home-based care
Passive smoke
Frequent smoke exposure
No smoke exposure
Current season
Fall or early winter
Spring or early summer
Physical symptoms
Ear pain, tugging, or pulling
Asymptomatic
Hearing
Bilateral hearing loss
Normal hearing
Speech and language
Speech delay or misarticulation
No speech impairment
Behavioral symptoms
Abnormal behavior
Normal behavior
Impact on child
School performance
Adversely affected
Unaffected
Otoscopic appearance
TM retraction or collapse
Air bubbles or air-fluid level
Antibiotic tolerance
Multiple drug allergies
Antibiotics well tolerated
Baseline otitis media risk
High-risk population
Normal risk
Other indication for surgery
on pharynx or ears
Present
Miscellaneous
*
Absent
TM = tympanic membrane.
*Cleft palate, immunodeficiency, Down syndrome, craniofacial anomalies, Eskimos, Native Americans.
child with unilateral or bilateral OME and a baseline sensorineural loss would benefit from early tympanostomy tube insertion, not prolonged
medical therapy. Adenoidectomy is effective for OME in older children [30] [47] [60] but is not recommended for those age 3 years or younger.
[79]
STEPWISE APPROACH TO RECURRENT AOM
A network of primary care doctors representing nine countries was asked to rate how certain they were when diagnosing AOM in young children.
Survey results indicated a disconcerting 58% level of diagnostic certainty in patients aged 0 to 12 months, rising to 66% at 13 to 30 months, and
73% for children more than 30 months of age. [29] These results illustrate the difficulty of diagnosing AOM in young children, not the
incompetence of the physicians surveyed. With recurrent AOM, the issue of diagnostic certainty is paramount because of a geometric increase in
the potential consequences.
Even a skilled otoscopist can struggle to glimpse the tympanic membrane in an uncooperative child with small ear canals or obstructing cerumen.
If obstructing cerumen cannot be removed easily, the child should be referred to an otolaryngologist for microscopic cleaning of the ear canal.
When the tympanic membrane is visualized, a test of middle ear function is performed to verify that a MEE is present (tympanometry or
pneumatic otoscopy). Unfortunately the severity of tympanic membrane inflammation predicts neither the presence of MEE nor the clinical course
of recurrent AOM. [3] A red eardrum commonly
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occurs during brisk crying and viral myringitis, which are self-limited conditions distinct from AOM.
Recognizing that problems with diagnostic certainty can never be completely avoided, the author recommends tailoring the treatment of recurrent
AOM episodes accordingly. When certainty is high, treatment of the episode should proceed as outlined earlier (see Table 5) . Examples include
purulent otorrhea, a bulging tympanic membrane, or acute symptoms with a documented MEE. When certainty is low, the caregiver may be given
a prescription for a first-line antibiotic and told to treat the child only if acute symptoms do not subside after 24 to 48 hours of expectant therapy.
This approach avoids unnecessarily treating viral myringitis and false-positive diagnoses of AOM. When certainty is moderate, judgment is
required. Infants and young children with severe symptoms should probably be treated, but older children with nonsevere symptoms may be
managed expectantly.
Primary prevention of recurrent AOM involves modifying risk factors and using vaccines (Table 8) . Children in group day care are at increased
risk for recurrent AOM, but the size of the group--not day care per se--is responsible. [42] [46] When the group size is six children or fewer, risk is
not increased. Pacifiers should be discouraged in day care settings, because their use accounts for 25% of recurrent AOM in children less than 3
years of age. [56] Children in day care also benefit from an influenza A vaccine, which reduces the incidence of AOM by about 40% during the
influenza season (January to February). [20] [34] In contrast, the pneumococcal vaccine (children 2 years or more) does not decrease overall
incidence of AOM but reduces vaccine-type pneumococcal AOM. [9] This may be beneficial given a rising prevalence of multidrug-resistant
pneumococcus. Finally, breast-feeding (4 months or longer) has been shown to reduce AOM frequency in longitudinal studies. [2] [22]
Enthusiasm for antibiotic prophylaxis of recurrent AOM must be tempered by reality: a child must be treated for 9 months, on average, to prevent
one AOM episode beyond what would occur from natural history alone. [74] Although
TABLE 8 -- STEPWISE APPROACH TO MANAGING RECURRENT ACUTE OTITIS MEDIA
Step
1. Confirm the diagnosis
Comment
Distinguish myringitis from true otitis media; confirm
MEE by tympanometry or pneumatic otoscopy
2. Put the odds in your favor
Limit passive smoke exposure; consider group daycare alternatives; discourage pacifier use in day
care
3. Practice prevention
Encourage breast feeding; control allergies; consider
pneumococcal vaccine (age 2 years or more) or
influenza vaccine (day care)
4. Use prophylaxis with caution
Risk of acclerated bacterial resistance often
outweighs minimal benefit of prolonged antibiotic
prophylaxis
5. Avoid unproven therapies
Antihistamine/decongestant combinations are of no
benefit; chiropractic, homeopathy, and naturopathy
are unproven
6. Fit the punishment to the
crime
Recurrent AOM with minimal symptoms can be
managed expectantly; consider surgery if
accompanied by febrile seizures, antibiotic
intolerance, hearing loss, speech problems, or
chronic OME
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statistically significant, the clinical significance is questionable when balanced against risks of accelerated bacterial resistance. Particular caution
applies to children in group day care, where bacterial resistance is already more common. [67] Intermittent prophylaxis during respiratory illness is
appealing but may be less effective than continuous treatment. [5] Furthermore, when OME persists between episodes of recurrent AOM,
prophylaxis does not increase resolution of the baseline effusion. [66] [83] These findings argue for judicious use of antibiotic prophylaxis on a
restrictive and individualized basis.
When medical options have been exhausted, surgery must be considered. Tympanostomy tubes are effective in controlling recurrent AOM, with or
without intercurrent OME, because they effectively bypass the child's immature and poorly functioning eustachian tube. [16] [31] [32] Breakthrough
episodes of AOM while on antibiotic prophylaxis are not a mandatory prerequisite to tube insertion because of the concerns about prophylaxis
expressed earlier. What is important, however, is the frequency and severity of AOM episodes and the presence or absence of associated sequelae,
such as hearing loss, speech problems, or multiple drug allergies. Adenoidectomy is effective for recurrent AOM in children who have had
tympanostomy tube insertion at least once previously. [60]
SUMMARY
More than 20 years ago, a shrewd clinician remarked, "There is little evidence that those antimicrobial agents which hypothetically or in vitro are
more effective . . . are superior in the treatment of otitis when compared to penicillin alone." [78] Several hundred clinical trials later, the
advantages of broad spectrum drugs remain unproved, and questions remain as to whether antibiotics are required for most episodes of AOM.
Further, antibiotics have been demoted to the status of optional therapy for OME. [79] This situation is unlikely to change as new studies with new
antibiotics proliferate.
What is clear, however, is that accelerated patterns of bacterial resistance mandate an evidence-based approach to managing otitis media. Bacteria
have an uncanny ability to learn new mechanisms of antibiotic resistance. [55] A large part of bacterial "education" has undoubtedly been fueled by
antibiotic prescriptions from well-intentioned physicians, with unrealistic expectations of drug efficacy. A judicious approach to antibiotic
treatment of otitis media can result only from knowing the spontaneous course of the disorder and incremental effect of antibiotics on clinical
outcomes.
In this article, a series of unifying concepts are developed to help practicing clinicians with an evidence-based approach to managing otitis media.
Critical review of the published evidence suggests that the most favorable outcomes from medical treatment will occur if practitioners:
appreciate the favorable natural history of untreated otitis media
realize that OME may take months to resolve following a single AOM episode
modify risk factors to improve the odds of spontaneous resolution
use pneumatic otoscopy and confirmatory tympanometry to diagnose OME
recognize the limited impact of antibiotic therapy on treatment and prevention
balance the benefits of antibiotics against the risk of accelerated bacterial resistance
P1178
avoid repetitive, prolonged, or prophylactic antibiotic treatment of chronic OME
avoid ineffective therapy, such as antihistamine/decongestant preparations
An important aspect of management is helping caregivers understand the natural history of otitis media and the impact of medical treatment on
short-term and long-term outcomes. Realistic expectations on the part of all involved parties should facilitate rational decisions about watchful
waiting, medical therapy, and the need for surgical intervention.
ACKNOWLEDGMENTS
Special thanks to the countless investigators who conduct and publish clinical trials and epidemiologic studies on otitis media, without whom an
evidence-based approach to treatment would be impossible. I am also indebted to Dr. Charles Bluestone for his insights and inspirations, which
underlie many of the concepts explored herein.
References
1. AAP Committee on Infectious Diseases: The use of acyclovir in otherwise healthy children with varicella. Pediatrics 91:674, 1993
2. Aniansson G, Alm B, Andersson B, et al: A prospective cohort study on breast-feeding and otitis media in Swedish infants. Pediatr Infect Dis J 13:183, 1994
3. Appelman CLM, Claessen JQPJ, Touw-Otten FWMM, et al: Severity of tympanic membrane inflammation as a predictor of clinical course of recurrent acute otitis media. Br Med J 306:895,
1993
4. Barnett ED, Klein JO, Teele DW, et al: Short course therapy for acute otitis media: Single dose ceftriaxone. In Abstracts of the Sixth International Symposium on Recent Advances in Otitis
Media, Fort Lauderdale, FL, 1995, p 119
5. Berman S, Nuss R, Roark R, et al: Effectiveness of continuous versus intermittent amoxicillin to prevent episodes of otitis media. Pediatr Infect Dis J 11:63, 1992
6. Bernstein JM: The role of IgE-mediated hypersensitivity in the development of otitis media with effusion. Otolaryngol Clin North Am 25:197, 1992
7. Blanshard JD, Maw AR, Bawden R: Conservative treatment of otitis media with effusion by autoinflation of the middle ear. Clin Otolaryngol 18:188, 1993
8. Block SL, Harrison CJ, Hedrick JA, et al: Penicillin-resistant Streptococcus pneumoniae in acute otitis media: Risk factors, susceptibility patterns and antimicrobial management. Pediatr Infect
Dis J 14:751, 1995
9. Bluestone CD, Klein JO: Management. In Otitis Media in Infants and Children, ed 2. Philadelphia, WB Saunders, 1995, pp 145-240
10. Bluestone CD, Klein JO: Microbiology. In Otitis Media in Infants and Children, ed 2. Philadelphia: WB Saunders, 1995, pp 55-72
11. Bluestone CD, Stephenson JS, Martin LM: Ten-year review of otitis media pathogens. Pediatr Infect Dis J 11(Suppl):7, 1992
12. Bodor FF: Systemic antibiotics for the treatment of the conjunctivitis-otitis media syndrome. Pediatr Infect Dis J 8:289, 1989
13. Boken DJ, Chartrand SA, Goering RV, et al: Colonization with penicillin-resistant Streptococcus pneumoniae in a child-care center. Pediatr Infect Dis J 14:879, 1995
14. Bradley JS, Kaplan SL, Klugman KP, et al: Consensus: Management of infections in children caused by Streptococcus pneumoniae with decreased susceptibility to penicillin. Pediatr Infect
Dis J 14:1037, 1995
15. Burke P, Bain J, Robinson D, et al: Acute red ear in children: Controlled trial of non-antibiotic treatment in general practice. Br Med J 303:558, 1991
16. Casselbrant ML, Kaleida PH, Rockette HE, et al: Efficacy of antimicrobial prophylaxis
P1179
and of tympanostomy tube insertion for prevention of recurrent acute otitis media: Results of a randomized clinical trial. Pediatr Infect Dis J 11:278, 1992
17. Chamberlain JM, Boenning DA, Waisman Y, et al: Single-dose ceftriaxone versus 10 days of cefaclor for otitis media. Clin Pediatr 33:642, 1994
18. Chaput de Saintonge DM, Levine DF, et al: Trial of three-day and ten-day courses of amoxycillin in otitis media. Br Med J 284:1078, 1982
19. Chonmaitree T, Owen MJ, Patel JA, et al: Effect of viral respiratory tract infection on outcome of acute otitis media. J Pediatr 120:856, 1992
20. Clements DA, Langdon L, Bland C, et al: Influenza A vaccine decreases the incidence of otitis media in 6- to 30-month-old children in day care. Arch Pediatr Adolesc Med 149:1113, 1995
21. Dawson-Saunders B, Trapp RG: Association and prediction. In Basic and Clinical Biostatistics, ed 2. Norwalk, Appleton & Lange, 1994, pp 161-185
22. Duncan B, Ey J, Holberg CJ, Wright AL, et al: Exclusive breast-feeding for at least four months protects against otitis media. Pediatrics 91:867, 1993
23. Eisenberg DM, Kessler RC, Foster C, et al: Unconventional medicine in the United States: Prevalence, costs, and patterns of use. N Engl J Med 328:246, 1993
24. Etzel RA, Pattishall EN, Haley NJ, et al: Passive smoking and middle ear effusion among children in day care. Pediatrics 90:228, 1992
25. Faden H, Doern G, Wolf J, et al: Antimicrobial susceptibility of nasopharyngeal isolates of potential pathogens recovered from infants before antibiotic therapy: Implications for the
management of otitis media. Pediatr Infect Dis J 13:609, 1994
26. Fekety R, Shah AB: Diagnosis and treatment of Clostridium difficile colitis. JAMA 269:71, 1993
27. Fria TJ, Cantekin EI, Eichler JA: Hearing acuity of children with otitis media with effusion. Arch Otolaryngol 111:10, 1985
28. Friel-Patti S, Finitzo T: Language learning in a prospective study of otitis media with effusion in the first two years of life. J Speech Hear Res 33:188, 1990
29. Froom J, Culpepper L, Grob P, et al: Diagnosis and antibiotic treatment of acute otitis media: Report from International Primary Care Network. Br Med J 300:582, 1990
30. Gates GA, Avery CA, Prihoda TJ, et al: Effectiveness of adenoidectomy and tympanostomy tubes in the treatment of chronic otitis media with effusion. N Engl J Med 317:1444, 1987
31. Gebhart DE: Tympanostomy tubes in the otitis media-prone child. Laryngoscope 91:849, 1981
32. Gonzalez C, Arnold JE, Woody EA, et al: Prevention of recurrent acute otitis media: Chemoprophylaxis versus tympanostomy tubes. Laryngoscope 96:330, 1986
33. Green SM, Rothrock SG: Single-dose intramuscular ceftriaxone for acute otitis media in children. Pediatrics 91:23, 1993
34. Heikkinen T, Ruuskanen O, Waris M, et al: Influenza vaccination in the prevention of acute otitis media in children. Am J Dis Child 145:445, 1991
35. Hendrickse WA, Kusmiesz H, Shelton S, et al: Five vs. ten days of therapy for acute otitis media. Pediatr Infect Dis J 7:14, 1988
36. Jensen PM, Lous J: Treatment of acute otitis media in Danish general practice. In Abstracts of the Sixth International Symposium on Recent Advances in Otitis Media, Fort Lauderdale, FL,
1995, p 123
37. Jones R, Bain J: Three-day and seven-day treatment in acute otitis media: A double-blind antibiotic trial. J Royal Coll Gen Pract 36:356, 1986
38. Kaleida PH, Casselbrant ML, Rockette HE, et al: Amoxicillin or myringotomy or both for acute otitis media: Results of a randomized clinical trial. Pediatrics 87:466, 1991
39. Kaplan SL, Mason EO Jr: Antimicrobial agents: Resistance patterns of common pathogens. Pediatr Infect Dis J 13:1050, 1994
41. Lieberman A, Bartal N: Untreated persistent middle ear effusion. J Laryngol Otolaryngol 100:875, 1986
42. Louhiala Pekka J, Jaakkola N, Ruotsalainen R, et al: Form of day care and respiratory infections in children. Am J Public Health 85:1109, 1995
43. Mandel EM, Casselbrant ML, Rockette HE, et al: Efficacy of 20- versus 10-day antimicrobial treatment for acute otitis media. Pediatrics 96:5, 1995
P1180
44. Mandel EM, Rockette HE, Paradise JL, et al: Comparative efficacy of erythromycin-sulfisoxazole, cefaclor, amoxicillin, or placebo for otitis media with effusion in children. Pediatr Infect
Dis J 10:899, 1991
45. Marchant CD, Carlin SA, Johnson CE, et al: Measuring the comparative efficacy of antibacterial agents for acute otitis media: The "Pollyana" phenomenon. J Pediatr 120:72, 1992
46. Marx J, Osguthorpe D, Parsons G: Day care and the incidence of otitis media in young children. Otolaryngol Head Neck Surg 112:695, 1995
47. Maw AR: Chronic otitis media with effusion (glue ear) and adenotonsillectomy: Prospective randomised controlled study. Br Med J 287:1586, 1983
48. McCaig LF, Hughes JM: Trends in antimicrobial drug prescribing among office-based physicians in the United States. JAMA 273:214, 1995
49. McCracken GH Jr: Emergence of resistant Streptococcus pneumoniae: A problem in pediatrics. Pediatr Infect Dis J 14:424, 1995
50. Murph JR, Dusdieker LB, Booth B, et al: Is treatment of acute otitis media with once-a-day amoxicillin feasible? Clin Pediatr 32:528, 1993
51. Mygind N, Meistrup-Larsen KI, Thomsen J, et al: Penicillin in acute otitis media: A double-blind placebo-controlled trial. Clin Otolaryngol 6:5, 1981
52. Nadal D, Herrmann P, Bauman A, et al: Acute mastoiditis: Clinical, microbiological, and therapeutic aspects. Eur J Pediatr 149:560, 1990
53. Nelson CT, Mason EO Jr, Kaplan SL: Activity of oral antimicrobials in middle ear and sinus infections caused by penicillin-resistant Streptococcus pneumoniae: Implications for treatment.
Pediatr Infect Dis J 13:585, 1994
55. Neu HC: The crisis in antibiotic resistance. Science 257:1064, 1992
56. Niemela M, Uhari M, Mottonen M: A pacifier increases the risk of recurrent acute otitis media in children in day care centers. Pediatrics 96:884, 1995
57. Ottolini MG, Ascher DP, Cieslak TJ, et al: Pneumococcal bacteremia during oral treatment with cefixime for otitis media. Pediatr Infect Dis J 10:467, 1991
58. Owen MJ, Chonmaitree T, Hornberger B, et al: Bacteriologic and clinical efficacy of ceftriaxone in treatment of acute otitis media. In Abstracts of the Sixth International Symposium on
Recent Advances in Otitis Media, Fort Lauderdale, FL, 1995, p 131
59. Paradise JL, Bluestone CD, Bachman RZ, et al: History of recurrent sore throat as an indication for tonsillectomy. N Engl J Med 298:409, 1978
60. Paradise JL, Bluestone CD, Rogers KD, et al: Efficacy of adenoidectomy for recurrent otitis media in children previously treated with tympanostomy-tube placement: Results of parallel
randomized and nonrandomized trials. JAMA 263:2066, 1990
61. Pichichero ME, Pichichero CL: Persistent acute otitis media: I. Causative pathogens. Pediatr Infect Dis J 14:178, 1995
62. Pichichero ME, Pichichero CL: Persistent acute otitis media: II. Antimicrobial treatment. Pediatr Infect Dis J 14:183, 1995
63. Post JC, Preston RA, Aul JJ, et al: Molecular analysis of bacterial pathogens in otitis media with effusion. JAMA 273:1598, 1995
64. Prellner K: Is beta-lactamase producing bacteria of major importance for unfavourable development of acute otitis media? Acta Otolaryngol (Stockh) 493:109, 1992
65. Principi N, Marchisio P, Bigalli, et al: Amoxicillin twice daily in the treatment of acute otitis media in infants and children. Eur J Pediatr 145:522, 1986
66. Principi N, Marchisio P, Massironi E, et al: Prophylaxis of recurrent acute otitis media and middle-ear effusion: comparison of amoxicillin with sulfamethoxazole and trimethoprim. Am J Dis
Child 143:1414, 1989
67. Reichler MR, Allphin AA, Breiman RF, et al: The spread of multiply resistant Streptococcus pneumoniae at a day care center in Ohio. J Infect Dis 166:1346, 1992
68. Reid R, Bradley JS, Hindler J: Pneumococcal meningitis during therapy of otitis media with clarithromycin. Pediatr Infect Dis J 14:1104, 1995
69. Rosenfeld RM, Madell JR, Green J: Auditory function in normal-hearing children with middle ear effusion. In Abstracts of the Sixth International Symposium on Recent Advances in Otitis
Media. 1995, Fort Lauderdale, FL, p 190
70. Rosenfeld RM, Mandel EM, Bluestone CD: Systemic steroids for otitis media with effusion in children. Arch Otolaryngol Head Neck Surg 117:984, 1991
P1181
71. Rosenfeld RM, Post JC: Meta-analysis of antibiotics for the treatment of otitis media with effusion. Otolaryngol Head Neck Surg 106:378, 1992
72. Rosenfeld RM, Vertrees JE, Carr J, et al: Clinical efficacy of antimicrobial drugs for acute otitis media: Meta-analysis of 5400 children from thirty-three randomized trials. J Pediatr 124:355,
1994
73. Rosenfeld RM: Nonsurgical management of surgical otitis media with effusion. J Laryngol Otolaryngol 109:811, 1995
74. Rosenfeld RM: What to expect from medical treatment of otitis media. Pediatr Infect Dis J 14:731, 1995
75. Rudberg RD: Acute otitis media: comparative therapeutic results of sulphonamide and penicillin administered in various forms. Acta Otolaryngol 113(Suppl):1, 1954
76. Spigelblatt L, Laine-Ammara G, Pless IB, et al: The use of alternative medicine by children. Pediatrics 96:811, 1994
77. Stangerup SE, Sederberg-Olsen J, Balle V: Autoinflation as a treatment of secretory otitis media: A randomized controlled study. Arch Otolaryngol Head Neck Surg 118:149, 1992
78. Stickler GB: How many more treatment trials in otitis media? Am J Dis Child 125:403, 1973
79. Stool SE, Berg AO, Berman S, et al: Otitis Media with Effusion in Young Children. Clinical Practice Guideline, Number 12. AHCPR Publication No. 94-0622. Rockville, MD: Agency for
Health Care Policy and Research, Public Health Service, US Department of Health and Human Services, July 1994
80. Teele DW, Klein JO, Rosner B: Epidemiology of otitis media in children. Ann Otol Rhinol Laryngol 89:5, 1980
81. Tenover FC, Hughes JM: The challenges of emerging infectious diseases: Development and spread of multiply-resistant bacterial pathogens. JAMA 275:300, 1996
82. Toner JG, Mains B: Pneumatic otoscopy and tympanometry in the detection of middle ear effusion. Clin Otolaryngol 15:121, 1990
83. Varsano I, Volovitz B, Mimouni F: Sulfisoxazole prophylaxis of middle ear effusion and recurrent acute otitis media. Am J Dis Child 139:632, 1985
84. Williams RL, Chalmers TC, Stange KC, et al: Use of antibiotics in preventing recurrent acute otitis media and in treating otitis media with effusion: A meta-analytic attempt to resolve the
brouhaha. JAMA 270:1344, 1993
85. Zenni MK, Cheatham SH, Thompson JM, et al: Streptococcus pneumoniae colonization in the young child: Association with otitis media and resistance to penicillin. J Pediatr 127:533, 1995
86. Zielhuis GA, Straatman H, Rach GH, et al: Analysis and presentation of data on the natural course of OME in children. Int J Epidemiol 19:1037, 1990
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